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Development of orally bioavailable bicyclic pyrazolones as inhibitors of tumor necrosis factor-alpha production |
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| Authors: | Clark Michael P Laughlin Steven K Laufersweiler Matthew J Bookland Roger G Brugel Todd A Golebiowski Adam Sabat Mark P Townes Jennifer A VanRens John C Djung Jane F Natchus Michael G De Biswanath Hsieh Lily C Xu Susan C Walter Rick L Mekel Marlene J Heitmeyer Sandra A Brown Kimberly K Juergens Karen Taiwo Yetunde O Janusz Michael J |
| Affiliation: | Health Care Research Center, Procter and Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA. clark.mp@pg.com |
| Abstract: | 2-Aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel bicyclic pyrazolone core, are described. Many showed low-nanomolar activity against lipopolysaccharide-induced TNF-alpha production in monocytic cells. Secondary screening data are presented for the pyrimidinyl bicyclic pyrazolones. Several of these analogues showed good oral bioavailability in rat and efficacy in the rat iodoacetate in vivo model. |
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